Numerous surface carbohydrates are expressed in malignant tumor cells. For example, Globo H (Fuc α1→2Galβ1→3GalNAcβ1→3Gal α1→4Galβ1→4Glc) has been shown to be overexpressed on a variety of epithelial cancers and is associated with tumor aggressiveness and poor prognosis in breast cancer and small cell lung carcinoma.
These findings support therapeutic rationales designed to counteract the activities of the tumor-associated carbohydrates. In particular, antibodies that bind to the tumor-associate carbohydrates are drawing more attentions as a means to treat or inhibit cancer cells, as they have longer half-life in plasma and fewer adverse effects. Some earliest antibodies were mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from lymphocytes of mice immunized with these tumor associated carbohydrates. However, there are problems associated with the use of mouse antibodies in human, such as inability to trigger certain human effector function and adverse reaction including cytokine releases syndrome. Antibodies derived from a nonhuman animal species are humanized to enhance the effector function utility and/or lower the adverse reaction. However, a humanized antibody does not have a comparable binding activity as the non-humanized antibody.
There is still an unmet need to optimize the binding affinity of a humanized antibody. The present invention provides antibodies with optimized binding affinity to satisfy these and other needs.